Common genetic variation in five thrombosis genes and relations to plasma hemostatic protein level and cardiovascular disease risk
Common genetic variation in five thrombosis genes and relations to plasma hemostatic protein level and cardiovascular disease risk
复制标题
DOI：
10.1161/01.atv.0000222011.13026.25
复制
发表时间：
2006-06-01
影响因子：
8.7
通讯作者：
O'Donnell, Christopher J.
中科院分区：
文献类型：
--
作者：
Kathiresan, Sekar;Yang, Qiong;O'Donnell, Christopher J.
目的 - 我们进行了连锁不平衡（LD） - 基于基于遗传学方法来研究以下假设：5个血栓形成基因中的常见序列变异会影响血浆止血蛋白水平或心血管疾病的风险或心血管疾病的风险（CVD）（CVD）（CVD）。Methods和结果 - 在参考小组中，我们表征了纤维蛋白原基因簇（纤维蛋白原[FGB]，FGA和FGG），因子VII（F7）和组织纤溶酶原激活剂（PLAP）基因座的LD结构。在1811年无关的Framingham心脏研究参与者中，对41个TAG单核苷酸多态性（SNP）进行了基因分型。有9 FGB SNP的显着关联，纤维蛋白原水平（最小p = 0.002）和7 F7 SNP和因子VII水平（最小p <0.0001）。平台位点的SNP与平台无关。在逐步分析中，单个FGB变体在纤维蛋白原水平上解释了1％的残留方差，而2个F7 SNP一起解释了VII因子水平的10％残留方差。两种平台单倍型与CVD相关（多变量调整的全局P = 0.0004）。结论 - 对常见序列变化的全面调查表明，顺式调节性SNP解释了循环纤维蛋白含量和因子VII水平和柏拉图单倍型的循环中残留方差的适度比例增加CVD的风险。需要进行其他研究以确认平台序列变化和CVD风险的关联。
Objective - We undertook a linkage disequilibrium (LD) - based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD).Methods and Results - In a reference panel, we characterized LD structure at the fibrinogen gene cluster (fibrinogen-beta[FGB], FGA, and FGG), factor VII (F7), and tissue plasminogen activator (PLAT) loci. Forty-one tag single nucleotide polymorphisms (SNPs) were genotyped in 1811 unrelated Framingham Heart Study participants. There were significant associations of 9 FGB SNPs with fibrinogen level (minimum P = 0.002) and of 7 F7 SNPs and factor VII level (minimum P < 0.0001). SNPs at the PLAT locus were not associated with PLAT level. In stepwise analysis, a single FGB variant explained 1% of the residual variance in fibrinogen level, and 2 F7 SNPs together explained 10% of the residual variance in factor VII level. Two PLAT haplotypes were associated with CVD (multivariable-adjusted global P = 0.0004).Conclusions - A comprehensive survey of common sequence variation demonstrates that cis-regulatory SNPs explain a modest proportion of the residual variance in circulating fibrinogen and factor VII level and PLAT haplotypes increase the risk of CVD. Additional studies are warranted to confirm the association of PLAT sequence variation and risk of CVD.